CD47 antisense oligonucleotide treatment improves glucose homeostasis and alleviates dyslipidemia in aged male mice

Abstract

As the global elderly population grows, age-associated metabolic disorders pose increasing public health challenges, highlighting the need for effective therapies. CD47, a transmembrane protein involved in immune and metabolic regulation, has been previously implicated in aging-related metabolic dysfunction. In this study, we investigated whether targeting CD47 by antisense oligonucleotide (ASO) could improve metabolic health in aged male mice. Twenty-month-old male mice were treated with control ASO or CD47 ASO (25 μg/g) for 10 weeks. We found that CD47ASO treatment selectively reduced visceral adiposity without affecting overall body weight in aged mice. It also improved glucose tolerance, insulin sensitivity, and hyperlipidemia—key metabolic disturbances commonly associated with aging. Mechanistically, CD47 ASO treatment reduced adipocyte size in visceral fat by suppressing lipogenesis rather than enhancing lipolysis, which was confirmed in vitro 3T3-L1 adipocyte model. It also stimulated hepatic glucose metabolism and improved brown adipose tissue (BAT) function by upregulating the expression of genes related to thermogenesis and endocrine signaling, including UCP1, CPT1β, and Neuregulin 4 (NRG4). Together, these findings support a beneficial role for CD47 knockdown in alleviating age-associated metabolic dysfunction through coordinated effects across multiple organs.